TGF-B receptor 1 regulates progenitors that promote browning of white fat

Authors: WANKHADE, UMESH - University Arkansas For Medical Sciences (UAMS); LEE, JI-HYEON - National Institutes Of Health (NIH); DAGUR, PRADEEP - National Heart, Lung And Blood Institute(NHLBI, NIH); YADAV, HARIOM - Wake Forest University; SHEN, MICHAEL - Duke University; CHEN, WEIPING - National Institutes Of Health (NIH); KULKARNI, ASHOK - National Institutes Of Health (NIH); MCCOY, J.PHILIP - National Heart, Lung And Blood Institute(NHLBI, NIH); FINKEL, TOREN - National Institutes Of Health (NIH); CYPESS, AARON - National Institutes Of Health (NIH); RANE, SUSHIL - National Institutes Of Health (NIH)

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/23/2018
Publication Date: 7/27/2018
Citation: Wankhade, U.D., Lee, J., Dagur, P.K., Yadav, H., Shen, M., Chen, W., Kulkarni, A.B., McCoy, J., Finkel, T., Cypess, A.M., Rane, S.G. 2018. TGF-B receptor 1 regulates progenitors that promote browning of white fat. Molecular Metabolism. https://doi.org/10.1016/j.molmet.2018.07.008.
DOI: https://doi.org/10.1016/j.molmet.2018.07.008

Interpretive Summary: The newborn period represents a time in which energy metabolism is critical to maintain body temperature. It is now appreciated that a specialized type of fat tissue, brown adipose tissue (BAT), is central to this process in that fat, sugar and amino acid metabolism in the BAT readily leads to robust heat production. Recently identified "beige" adipocytes are known to display traits of classical brown adipocyte and aid body in calorie-consuming heat production in adults. The specific regulators that switch on beige fat development are not known, but could involve hormones and other factors responsive to diet and energy intake. In the current manuscript, we identified the key role of a factor called TGFB in terms of signaling in presumptive beige fat progenitor (precursor) cells. Absence of TGFB in these cells seems to promote their fate toward beige cells. Upon genetic or pharmacologic inhibition of TGF-B signaling, these cells express high levels of predominantly beige markers. Upon transplanting TGFB-deleted cells into nude mice (mice with no immune system and therefore will not reject transplanted tissue), progenitor cells differentiated into beige cells and displayed metabolically beneficial gene expression. Findings from this study provide critical insights into the critical role of TGFB signaling in fate determination of pre-adipocytes, and future studies can evaluate how these pathways to promote thermogenic fat tissue can be regulated throughout the lifespan. Higher abundance of beige fat could in theory help combat obesity development and improve blood sugar control in at-risk individuals.

Technical Abstract: Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-B signaling regulates the browning of white adipose tissue. Here, we inquired whether TGFB signals regulated presumptive beige progenitors in white fat and investigated the TGF-B regulated mechanisms involved in beige adipogenesis. We deleted TGF-B receptor 1 (TßRI) in adipose tissue (TBRIAdKO mice) and using flow-cytometry based assays identified and isolated presumptive beige progenitors located in the stromal vascular compartment of white fat. These cells were molecularly characterized to examine beige/brown marker expression and to investigate TGF-B dependent mechanisms. Further, the cells were transplanted into athymic nude mice to examine their adipogenesis potential. Deletion of TBRI promotes beige adipogenesis while reducing the detrimental effects of high fat diet feeding. Interaction of TGF-B signaling with the prostaglandin pathway regulated the appearance of beige adipocytes in white fat. Using flow cytometry techniques and stromal vascular fraction from white fat, we isolated presumptive beige stem/progenitor cells (iBSCs). Upon genetic or pharmacologic inhibition of TGF-B signaling, these cells express high levels of predominantly beige markers. Transplantation of TBRI-deficient stromal vascular cells or iBSCs into athymic nude mice followed by high fat diet feeding and stimulation of B-adrenergic signaling via CL316,243 injection or cold exposure promoted robust beige adipogenesis in vivo. TBRI signals target the prostaglandin network to regulate presumptive beige progenitors in white fat capable of developing into beige adipocytes with functional attributes. Controlled inhibition of TBRI signaling and concomitant PGE2 stimulation has the potential to promote beige adipogenesis and improve metabolism.